title: Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
abstract: This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland. heinrich.rueeger@novartis.com
authors.forename: Heinrich
authors.initials: H
authors.lastname: Rueeger
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.forename: Henrik
authors.initials: H
authors.lastname: Möbitz
authors.forename: Marina
authors.initials: M
authors.lastname: Tintelnot-Blomley
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001596:Benzylamines; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human